Better Supplementation with PEGylated Liposomes
How a new delivery vehicle provides greater bioavailability and sustained action through stealth technology
By Will Block

hile rummaging through your pantry, in a hungry sort of way, you discover an oatmeal-raisin cookie that had fallen behind a box a few days ago, unnoticed. You go for it like a politician grabbing at money, and devour it. Yum! But what if you should also find an errant cookie that had been lying there for a few weeks—a cookie that now has a coat of greenish fuzz on it? Yuck! No way will you eat that cookie—you eat only good stuff.

Inside your body, however, things are just the reverse. Billions of specialized white blood cells called phagocytes (from the Greek for “cell-eater”) roam your bloodstream, in a ravenous sort of way, looking for bad things to eat, such as cellular waste material, potentially harmful microorganisms, and foreign substances that need to be expelled. When a phagocyte encounters something that, in its biochemical “opinion,” does not pass muster, it devours the offending item by engulfing and absorbing it. Bye-bye, offender! Eventually, the bad stuff is excreted, while you remain blissfully unaware of the countless, tiny life-and-death dramas that led to that, uh, outcome.

The Problem: Liposomes Are Therapeutic, but Artificial …

One problem with this otherwise fine bodily system (which is but one of many internal defense mechanisms for helping to keep you healthy) is that your phagocytes have a mind of their own, so to speak. They cannot be taught to ignore things that may look harmful, from their unique point of view, but that are actually good for you—things such as therapeutic liposomes, for example.

Liposomes are manmade cells that act as delivery vehicles for drugs or nutritional supplements. The cell walls of these microscopic spheres consist mainly of the natural substance lecithin, which is a mixture of phospholipids, predominantly phosphatidylcholine. This is the same fatty substance that is the primary constituent of cell walls (also called cell membranes) throughout the plant and animal kingdoms.

Despite their benign chemical composition, liposomes are viewed with suspicion by phagocytes because they’re artificially made. Phagocytes, God bless ’em, prefer that your blood carry only natural entities they deem suitable for your well-being. What they don’t know, however, is that liposomes—or, to be exact, the liposomes’ internal “payloads” of drugs or supplements—are intended for your well-being. So the phagocytes (motto: “If it looks disgusting, eat it!”) do their thing, and the tissues for which the medicinal or nutritional payload was intended go without.

… So Their Time in the Circulation Is Short

Not that it’s that simple or absolute, but that’s the gist of it. And it comes down to a matter of time: the more quickly the liposomes are devoured by phagocytes, the less of their payload will be released into the bloodstream. Some of the liposomes will accomplish their mission, but many will not. One obvious solution would be to increase your intake of liposomes so as to stay ahead of the phagocytes’ eating spree. But there’s an equally obvious catch: drugs and supplements are costly, so we want to minimize, not maximize, the amounts that have to be taken in order to achieve the desired results.

The Solution: Disguise Them through PEGylation

Enter PEGylation, an odd word denoting a clever “stealth technology” for (among other things) making liposomes less suspect to phagocytes. This is done by cloaking the liposomes in a kind of molecular “fuzz” consisting of a nontoxic, synthetic polymeric compound called polyethylene glycol (PEG). The cloudlike coating on the liposomes appears to the phagocytes to be harmless—and it is harmless, just like the liposomes themselves.*

*PEG shows so little toxicity that the FDA long ago approved it for use as a vehicle or base in foods, pharmaceuticals, and cosmetics. Many other similarly approved synthetic polymers have also been in use for decades, with no ill effects.

Thus, while people won’t eat fuzzy cookies because they look bad, phagocytes won’t eat fuzzy liposomes because they look good. Left unmolested, the tiny liposomal fuzz balls have a much greater chance of releasing their therapeutic payloads, so the amount that’s needed to begin with can be minimized. (By now the alert reader will have noticed a bizarre paradox in this story. For the explanation, see the sidebar, “The Case of the Confused Phagocytes.”)

The Case of the Confused Phagocytes

Cutaway diagram of a PEGylated liposome, showing molecules of the active agent (red) entrapped in the aqueous interior of a lipid bilayer (the liposome), whose outer surface is PEGylated (green “spaghetti”). The water of hydration on the PEG molecules is not shown.

Reading the accompanying article, you will no doubt have been struck by a paradox. Phagocytes, the cell-eating cells whose mission is to seek and destroy potentially harmful cellular matter and foreign substances, tend to devour uncoated liposomes, which are synthetic cells. That would make sense, but for the fact that the liposomal membrane (the only thing the phagocytes “see”) consists mainly of lecithin, the same natural substance of which all natural cell membranes, including those of the phagocytes themselves, are mainly made.

So the phagocytes’ hostility toward liposomes seems pretty strange—but what’s really bizarre is that these same phagocytes give a free pass to PEGylated liposomes, even though PEG (polyethylene glycol) is a synthetic polymer that’s unnatural (but quite harmless) in the human body.

What gives here—have our phagocytes become Unclear on the Concept? Not really. For starters, the surface of an uncoated liposome is very smooth compared with that of a typical natural cell, because natural cell membranes are bumpy—they’re studded with countless protein and carbohydrate complexes that give each type of cell a unique chemical identity by which it can be recognized by various other biological entities. In addition, liposomal membranes typically contain some nonlecithin compounds for purposes of stability; although innocuous, these molecules may seem suspicious enough to induce phagocytes—which are amazingly “smart,” but not perfect—to attack. Finally (and this may or may not be a factor), liposomes tend to be perfectly spherical, unlike most natural cells, whose shapes are distorted by internal structural components.

OK, one down, one to go. Now, what’s the phagocytes’ excuse for not attacking PEGylated liposomes? First, you need to know that the PEG molecules are very long and thin and are attached to the liposomal membrane at only one end. They’re also very flexible, like cooked spaghetti, so they sort of slosh around the liposome like … well, cooked spaghetti. Water is the key here, because water molecules are attracted to the PEG molecules through weak intermolecular forces. The cumulative effect of all that water (called water of hydration) clinging to the PEG molecules is to form an aqueous “cloak” that tends to mask PEG’s true identity as a compound alien to the human body.

So when the phagocytes encounter PEGylated liposomes, they “see” what appears to be a big blob of water rather than PEG (let alone liposome). They find this quite uninteresting and move on (whew!) in search of something nasty to eat. And that is one of the key factors in the remarkable efficacy of PEGylated liposomes as delivery vehicles for drugs and supplements.

That, in a nutshell, is the basis for a revolutionary, sustained-action pharmaceutical delivery technology called PEGylated liposomes, which has been under development since the 1970s (it first came into clinical use in the 1990s).1-5 This technology is just as well suited for the delivery of nutritional supplements as it is for drugs, because the liposomes don’t care what their payload is. Water-soluble nutrients are dissolved in the aqueous interior, and fat-soluble nutrients may be suspended (as fine particles) in the interior or dissolved in the liposomal membrane itself.

The Oral Route Can Be Bad for Bioavailability …

Physicians and pharmacists have always been concerned about the manner of delivery of medicinal agents and the efficiency with which they actually get delivered to the tissues or organs that need them. Quite apart from the many different physical forms that such agents can take and the different routes for introducing them into the body, there’s always the vexing question of bioavailability—how much of the agent will actually be delivered, and how much will be excreted as waste?

The bioavailability question is particularly relevant to the most common method of taking drugs or supplements: the oral route. What if some of the chemical compound in question is destroyed by stomach acid or digestive enzymes? What if some of what’s left is unable to pass from the intestine into the bloodstream? What if some of what’s left from that is altered or destroyed in the liver, which gets first crack at everything that enters the blood via the GI tract? And what if some of what’s left from that is subsequently attacked and degraded in the bloodstream, or removed by the kidneys, before it has a chance to fulfill its mission?

… As Can Other Factors, Such as Your Age

Get the picture? Now substitute “much” for “some” in the preceding paragraph, and it’s easy to see why, in many cases, only a tiny percentage of what you take actually gets to where it’s needed—which is why the amounts you have to take are often so large. To further complicate matters, the bioavailability of a given chemical compound may be quite different in different individuals, and it may depend on factors such as the time of day, whether or not the compound was taken with a meal, and whether or not the meal had a substantial fat content—some compounds become much more bioavailable in the presence of fat, because they’re soluble in fat but not in water.

Bioavailability may also depend on your state of health, and with many nutrients, it definitely depends on your age. Many chemical compounds in our food—most notoriously the B-vitamins B12 and folic acid—become dramatically less bioavailable as we grow older, owing mainly to poor absorption by the aging gut. Without adequate supplementation to compensate for such losses, the elderly can become severely deficient in B-vitamins and other vital nutrients, and their health and potential longevity will suffer as a result. That’s part of what has long been called “normal aging,” but it need not—and should not—be considered normal!

PEGylated Liposomes Deliver the Goods

The problems of poor and variable bioavailability of drugs and supplements—and of many of the nutrients in the foods we eat to begin with—are frustrating to doctors and pharmacists (and supplement designers and manufacturers), who naturally want to do right by their patients and customers by giving them only what they need, in optimal amounts, without too much of it going to waste. Hence the never-ending search for better ways to “deliver the goods.”

Which brings us back to PEGylated liposomes. Because the digestive tract is hostile to them too, they are not taken orally, but are commonly delivered by injection. But wait—don’t freak out!—they can also be taken transdermally or transmucosally, i.e., through the skin or mucous membranes (they can be formulated as gels or suspensions, by the way). By avoiding the digestive tract and introducing the liposomes’ payloads into the bloodstream via these more direct routes, it’s possible to increase bioavailability—and hence systemic exposure—greatly.

This confers an obvious clinical advantage, particularly in the case of many antioxidants and vitamins, which are not water-soluble and are poorly absorbed by the gut. And it confers an obvious economic advantage, because less of the active agent is needed to obtain the same or better results. Hence the patient or customer gets more bang for fewer bucks.

How Liposomes Work

One might think that making artificial cells would be terribly difficult. Your typical cell is, after all, an extremely complex entity embodying thousands of different chemical compounds interacting in myriad ways so as to create the phenomenon we call life. Indeed, creating a living cell from scratch is far beyond the capabilities of modern science. But liposomes are another matter, because they’re very simple in structure and easy to make.

Like a real cell, a liposome consists of a lipid bilayer—a two-molecule-thick membrane, delicate yet amazingly strong—enclosing an aqueous interior that incorporates the drug or supplement payload. As we have seen, this cell wall can be modified by the attachment of PEG molecules, allowing the liposomes to avoid being eaten by phagocytes. As the liposomes gradually break down and release their payloads into the bloodstream, these molecules can be taken up by the tissues that need them. That’s the simple method, which is used for delivering nutritional supplements.

A much more sophisticated method, used for many prescription drugs, and requiring great expertise in organic chemistry, is to cause the liposomes to release their payload only at specifically targeted tissues or organs. This can be done (in many cases) by using chemically modified forms of PEG, of which many varieties have been synthesized by chemists. In some cases it’s necessary to make the liposomes shed their cloak of modified PEG molecules when they reach their target, so that they can interact with the target and release their payload. This “reversible PEGylation” technique can be accomplished through chemical properties ingeniously incorporated into the liposomes.

Next Month: Real-Life Examples of Liposomal Benefits

Now that we’ve seen what liposomes are and how they can be disguised through PEGylation so as to increase the bioavailability of their payloads, we should look at some real-life examples of the ways in which this pharmaceutical stealth technology is being used to combat disease and improve human health. That will be covered in next month’s issue of Life Enhancement. Meanwhile, in case you missed them, two recent articles that discussed liposomes in some detail are
“A Better Way to Take Progesterone” (October 2004) and
“Coenzyme Q10 Sparks the Life Within You” (May 2005).